Polycaprolactone and polycaprolactone triol blends to obtain a stable liquid nanotechnological formulation: synthesis, characterization and in vitro - in vivo taste masking evaluation.

The use of polymeric blends is a potential strategy to obtain novel nanotechnological formulations aiming at drug delivery systems. Saquinavir, an antiretroviral drug, was chosen as a model drug for the development of new stable liquid formulations with unpleasant taste masking properties. Three formulations containing different polymeric ratios (1:3, 1:1 and 3:1) were prepared and properly characterized by particle size distribution, zeta potential, pH, drug content and encapsulation efficiency measurements. The stability was verified by monitoring the zeta potential, particle size distribution, polydispersity index and drug content by 90 days. The light backscattering analysis was used to early identify possible phenomena of instability in the formulations. The in vitro drug release and saquinavir cytotoxicity were evaluated. The in vitro and in vivo taste masking properties were studied using an electronic tongue and a human sensory panel. All formulations presented nanometric sizes around 200 nm and encapsulation efficiency above 99%. The parameters evaluated for stability remained constant throughout 90 days. The in vitro tests showed a controlled drug release and absence of toxic effects on human T lymphocytes. The electronic tongue experiment showed taste differences for all formulations in comparison to drug solutions, with a more pronounced difference for the formulation with higher polycaprolactone content (3:1). This formulation was chosen for in vivo sensory panel evaluation which results corroborated the electronic tongue experiments. In conclusion, the polymer blend nanoformulation developed herein showed the promising application to incorporate drugs aiming at pharmaceutical taste-masking properties.

Anti-hyperalgesic properties of ethanolic crude extract from the peels of Citrus reticulata (Rutaceae).

The therapeutic effects from Citrus reticulata on painful inflammatory ailments are associated to its flavonoids constituent and phytochemical studies with Citrus genus affirm that the peels have important amounts of it. These bioactive compounds have been a considerable therapeutic source and evaluate potential application of the peel extract is significant. This research aims to investigate the influence of ethanolic crude extract from the peels of Citrus reticulata and its possible mechanism of action in different animal models of pain. The extract reduced hyperalgesia in the second phase of formalin test (vehicle: 501.5 ± 40.0 s; C. reticulata extract 300 mg/kg: 161.8 ± 41.1 s), in the carrageenan model (vehicle at 4th h: 82.5 ± 9.6 %; C. reticulata extract 300 mg/kg at 4th h: 47.5 ± 6.5 %) and in Complete Freund's Adjuvant model (vehicle: 501.5 ± 40.0 s; C. reticulata extract 300 mg/kg: 161.8 ± 41.1 s). The possible contribution of opioidergic and adenosinergic systems in the anti-hyperalgesic effect of C. reticulata extract was observed after treatment, with non-selective antagonists for both systems, which produced reversal effects. In conclusion, these properties of C. reticulata extract suggest a potential therapeutic benefit in treating painful conditions.

Study of the potential adverse effects caused by the dermal application of Dillenia indica L. fruit extract standardized to betulinic acid in rodents.

This study aimed to evaluate the potential adverse effects of the dermal administration of Dillenia indica Linnaeus (D. indica) fruit extract in healthy rodents; the extract was standardized to betulinic acid. In the initial phase, the acute effects were evaluated on the skin application site of a single extract dose. A skin irritation test was performed in male Wistar rats (n = 8/group) receiving the extract (50-150 mg/mL) with betulinic acid (0.5-1.5%, respectively). A photosensitivity test was performed in male BALB/c mice (n = 6/group) receiving the extract (150 mg/mL). Afterwards, other BALB/c mice (n = 20, male:female, 1:1) were used to assess the systemic alterations caused by 14 daily repeated doses (150 mg/mL) by monitoring the effects on mortality, body morphology, behavior, nutrition status, neuromotor reactions, organ morphology and weight, and blood tests. At this time, 0.5 mg/mL clobetasol was used as the positive control. The skin irritation index suggested that negligible skin irritation had occurred, even when the extract was applied to the rat skin at 150 mg/mL. However, the extract acted as a photosensitizer on mouse skin, showing a photosensitizing activity close to that of 10 mg/mL 5-methoxypsoralen. Repeated doses caused no mouse mortality, aggressiveness, piloerection, diarrhea, convulsions, neuromotor alterations or nutrition status changes. The mouse organ weights did not change, and the mice did not have alterations in their blood compositions. Clobetasol caused a reduction in the mononuclear leukocyte numbers. In general, the data suggest that the extract was safe in healthy rodents but indicate that caution should be taken with the photosensitizing activity; in addition, this activity should be further explored as it may be useful for phototherapeutic drug development.

Cellulose acetate butyrate/poly(caprolactonetriol) blends: Miscibility, mechanical properties, and in vivo inflammatory response.

This study reports the results of the characterization of cellulose acetate butyrate and polycaprolactone-triol blends in terms of miscibility, swelling capacity, mechanical properties, and inflammatory response in vivo. The cellulose acetate butyrate film was opaque and rigid, with glass transition (T g ) at 134℃ and melting temperature of 156℃. The cellulose acetate butyrate/polycaprolactone-triol films were transparent up to a polycaprolactone-triol content of 60%. T g of the cellulose acetate butyrate films decreased monotonically as polycaprolactone-triol was added to the blend, thus indicating miscibility. FTIR spectroscopy revealed a decrease in intramolecular hydrogen bonding in polycaprolactone-triol, whereas no hydrogen bonding was observed between cellulose acetate butyrate and -OH from polycaprolactone-triol. The increase in polycaprolactone-triol content in the blend decreased the water uptake. An increase in polycaprolactone-triol content decreased the modulus of elasticity and increased the elongation at break. A cellulose acetate butyrate/polycaprolactone-triol 70/30 blend implanted in rats showed only an acute inflammatory response 7 days after surgery. No change in inflammation mediators was observed.

Evaluation of time toxicity, residual effect, and growth-inhibiting property of Carapa guianensis and Copaifera sp. in Aedes aegypti.

Oils of Carapa guianensis and Copaifera spp. are well-known in the Amazonian region as natural insect repellents, and studies have reported their efficiency as larvicide against some mosquito species. However, toxicity persistence and effect on mosquito development have not yet been evaluated. Thus, the objective of this study was to evaluate the initial time of larvicidal activity, residual effect, and the effect of very low concentrations of these oils on Aedes aegypti. Different concentrations of the oils were used to evaluate the initial time of larval mortality and residual effect, as well as, the development of larvae, pupae, and adults. Results demonstrated that the lethal effect started mainly between the first 2 and 3 h of larvae exposure to oils, when using concentrations which ranged from 500 mg/L of C. guianensis and 90 mg/L of Copaifera sp. The toxic effect remained with total efficiency (100% mortality) until the sixth day for Copaifera sp. and 12th day for C. guianensis. When using sublethal dosages (ranging from 140 mg/L of C. guianensis to 26 mg/L of Copaifera sp.) mortality was observed after the larval molt. Also, imperfection of pupae and adult development and unsuccessful emergence of adults were observed. A product of botanical origin that could break the development of immature stage of mosquitoes and inhibit the emergence of adults should be essential in vector control. Thus, our results provide new information for a better understanding in using C. guianensis and Copaifera sp. oils with a potential to be used as a natural insecticide.

First report on susceptibility of wild Aedes aegypti (Diptera: Culicidae) using Carapa guianensis (Meliaceae) and Copaifera sp. (Leguminosae).

Oils of Carapa guianensis and Copaifera spp. are well known in the Amazonian region as natural insect repellent, and studies have reported their efficiency as larvicide against some laboratory mosquito species. However, in wild populations of mosquitoes, these oils have not yet been evaluated. Thus, the objective of this study was to investigate their efficiency as larvicide in wild populations of Aedes aegypti with a history of exposure to organophosphate. The susceptibility of larvae was determined under three different temperatures, 15°C, 20°C, and 30°C. For each test, 1,000 larvae were used (late third instar and early fourth instar-four replicates of 25 larvae per concentration). Statistical tests were used to identify significant differences. The results demonstrated that as the laboratory A. aegypti, the wild populations of A. aegypti were also susceptible to C. guianensis and Copaifera sp. oils. The lethal concentrations for Copaifera sp. ranged from LC(50) 47 to LC(90) 91 (milligrams per liter), and for C. guianensis, they were LC(50) 136 to LC(90) 551 (milligrams per liter). In relation to different temperature, the effectiveness of the oils on larvae mortality was directly related to the increase of temperature, and better results were observed for temperature at 25°C. The results presented here indicate the potential larvicidal activity of C. guianensis and species of Copaifera, in populations of A. aegypti from the wild. Therefore, the results presented here are very important since such populations are primarily responsible for transmitting the dengue virus in the environment.

Método espectroscópico para determinação de cumarina em xarope de Mikania glomerata Sprengel / Ultraviolet spectroscopy method for coumarin quantification in Mikania glomerata Sprengel syrup

Este trabalho teve como objetivo desenvolver uma metodologia analítica por espectroscopia UV, para doseamento de cumarina em xaropes de Mikania glomerata. A técnica foi baseada na extração da cumarina utilizando solventes como o clorofórmio e hexano. Após a seleção do solvente, o comprimento de onda foi definido através da sobreposição dos espectros da cumarina, metil parabeno, diluição do xarope e solução extrativa do xarope. Foram preparadas curvas analíticas de cinco soluções de cumarina com concentração variando de 0,002 a 0,03 mg/mL. Para análise da exatidão do método, foram preparados três lotes de xarope de Mikania glomerata Sprengel e o teor de cumarina determinado pela técnica espectrofotométrica foi comparado a técnica por cromatografia líquida de alta eficiência. O solvente selecionado para extração foi o clorofórmio, o comprimento de onda 320 nm. A curva analítica apresentou R² de 0,99978, demonstrando linearidade. A comparação estatística do doseamento da cumarina pela técnica espectrofotométrica estudada com a técnica cromatográfica desenvolvida por Celeghini et al. (2001) demonstrou não existir diferenças significativas, indicativo de exatidão da técnica.

A spectrophotometric procedure for coumarin determination in Mikania glomerata Sprengel (guaco) syrup is described in this work. Due to the high number of constituents in guaco syrups, the coumarin was extracted with apolar extractors (chloroform and hexane), in which chloroform was selected, because of its higher capacity of extraction. After the solvent choice, the wavelength at 320 nm, region where there is the lower interference of syrup constituents, was selected. The calibration curve showed linearity, R² of 0.99978. The spectrophotometric assay of coumarin in three samples of Mikania glomerata Sprengel syrup showed accuracy compared with the HPLC method. The results presented suggest that the spectrophotometric method may be useful for the quantitative analysis of coumarin in Mikania glomerata Sprengel syrup.

Poly(ethylene-co-methyl acrylate) membranes as rate-controlling barriers for drug delivery systems: characterization, mechanical properties and permeability.

Poly(ethylene-co-methyl acrylate) (EMA) membranes with different amounts of methyl acrylate (MA) content were studied in terms of the thermal and mechanical properties, swelling and drug permeation. The increase in MA content in the copolymer significantly increased the percentage of elongation and decreased the tensile strength and modulus of elasticity of the membranes. The degree of swelling of the EMA membranes increased with the ethanol composition and MA content. The contact angle of a sessile drop (10 microL of ethanol/water solution) decreased with an increase in the ethanol fraction suggesting that the membrane wettibility increased with the ethanol content. The flux of diltiazem hydrochloride increased from 0.012 to 0.018 mg cm(-2)h(-1) with an increase in the MA content from 16.5 to 29.0%. By increasing the ethanol fraction from 0.4 to 1.0, the flux of diltiazem hydrochloride into the membranes with 29.0% MA, increased from 2.56 (+/-0.09) x 10(-3) to 18.38 (+/-0.62) x 10(-3) mg cm(-2)h(-1). The permeability coefficient increased from 5.85 x 10(-6) to 3.53 x 10(-4) cm h(-1) with an increase in the ethanol fraction. The flux can also be correlated with the drug solubility in the membrane and ethanol. For example, the solubilities of diltiazem hydrochloride, paracetamol and ibuprofen were 0.64, 6.68 and 504.48 mg cm(-3) in the membrane, respectively. Under the same conditions, the flux for the above mentioned drugs was 0.08 (+/-0.01), 0.53 (+/-0.01) and 45.11 (+/-2.00) mg cm(-2)h(-1).

Characterization and drug-permeation profiles of microporous and dense cellulose acetate membranes: influence of plasticizer and pore forming agent.

The use of pore forming agents and plasticizers are efficient ways to obtain membranes for controlled drug permeation through polymeric membranes. The challenge of the present study was to combine these two strategies to obtain cellulose acetate (CA) membranes, where poly(caprolactone triol) (PCL-T) was used as a plasticizer and water, dissolved in a casting solution, was used as a pore forming agent. First, the influence of water on membrane morphology, porosity and the permeation coefficient of a model drug (paracetamol) was analyzed. The influence of different amounts of PCL-T on the permeation coefficient of the CA membranes was then evaluated. Finally, both strategies were combined to obtain porous CA/PCL-T membranes. The membrane microstructure was analyzed using scanning electron microscopy (SEM), the CA crystallinity was determined via differential scanning calorimetry (DSC), and membrane permeability was investigated using paracetamol. The addition of water, a non-solvent, during the membrane casting process was found to be a simple and effective way to change membrane porosity and consequently the drug-permeation profile. When small quantities of non-solvent were used to obtain low porosity membranes, the presence of a plasticizer agent could be used to better modulate drug permeation. Combining the addition of PCL-T with the use of a non-solvent resulted in a series of CA membranes with paracetamol-permeation coefficient values in the range of ca. 10(-7) to 10(-5) cm s(-1).